Scientific Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear, α,β‐unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting) structurally related to

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ADOPTED: 14 November 2019 doi: 10.2903/j.efsa.2020.5924

Scienti ﬁ c Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear,

a , b -unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting)

structurally related to ﬂ avouring substances evaluated in FGE.05Rev3

EFSA Food Additive and Flavourings (EFSA FAF Panel),

Maged Younes, Gabriele Aquilina, Laurence Castle, Karl-Heinz Engel, Paul Fowler, Maria Jose Frutos Fernandez, Peter F€urst, Ursula Gundert-Remy, Rainer G€urtler, Trine Husøy,

Peter Moldeus, Agneta Oskarsson, Romina Shah, Ine Waalkens-Berendsen, Detlef W€olﬂe, Romualdo Benigni, Claudia Bolognesi, Kevin Chipman, Eugenia Cordelli, Gisela Degen,

Daniel Marzin, Camilla Svendsen, Carla Martino and Wim Mennes

Abstract

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 39flavouring substances assigned to the Flavouring Group Evaluation 71 (FGE.71), using the Procedure in Commission Regulation (EC) No 1565/2000. Nine substances have already been considered in FGE.71 [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235, 09.239]. The remaining 30 substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] have been cleared with respect to genotoxicity in FGE.200Rev1 and they are considered in this revision. The substances were evaluated through a stepwise approach that integrates information on the structure–activity relationships, intake from current uses, toxicological threshold of concern (TTC), and available data on metabolism and toxicity. The Panel concluded that none of the 39 substances gives rise to safety concerns at their levels of dietary intake, estimated on the basis of the ‘Maximised Survey-derived Daily Intake’(MSDI) approach. Besides the safety assessment of theflavouring substances, the specifications for the materials of commerce have also been considered and found adequate, except for [FL-no: 08.073 and 09.235]. For these two substances, data on the composition of the stereoisomeric mixture should be requested. Normal and maximum use levels should be provided for nineflavouring substances [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235, 09.239]. For two flavouring substances [FL-no: 02.020 and 05.076], the‘modified Theoretical Added Maximum Daily Intake’(mTAMDI) estimates are above the TTC for their structural class I. Therefore, additional information on uses and use levels should be provided for these eleven substances in order tofinalise their evaluation.

Keywords: ﬂavourings,ab-unsaturated carbonyls and precursors, FGE.71, JECFA

Requestor:European Commission

Question numbers: EFSA-Q-2018-00892, EFSA-Q-2018-00891, EFSA-Q-2018-00890, EFSA-Q-2018-00889, EFSA-Q-2018-00888, EFSA-Q-2018-00887, EFSA-Q-2018-00886, EFSA-Q-2018-00885, EFSA-Q-2018-00884,

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EFSA-Q-2018-00883, EFSA-Q-2018-00882, EFSA-Q-2018-00881, EFSA-Q-2018-00880, EFSA-Q-2018-00879, EFSA-Q-2018-00878, EFSA-Q-2018-00877, EFSA-Q-2018-00876, EFSA-Q-2018-00875, EFSA-Q-2018-00874, EFSA-Q-2018-00873, EFSA-Q-2018-00872, EFSA-Q-2018-00871, EFSA-Q-2018-00870, EFSA-Q-2018-00869, EFSA-Q-2018-00868, EFSA-Q-2018-00867, EFSA-Q-2018-00866, EFSA-Q-2018-00865, EFSA-Q-2018-00864 and EFSA-Q-2018-00863

Correspondence: ﬁp@efsa.europa.eu

Panel members: Gabriele Aquilina, Laurence Castle, Karl-Heinz Engel, Paul Fowler, Maria Jose Frutos Fernandez, Peter F€urst, Rainer G€urtler, Ursula Gundert-Remy, Trine Husøy, Wim Mennes, Peter Moldeus, Agneta Oskarsson, Romina Shah, Ine Waalkens-Berendsen, Detlef W€olﬂe and Maged Younes.

Acknowledgements: The Panel wishes to thank the hearing experts: Vibe Beltoft, Karin Nørby and EFSA staff Giorgia Vianello for the support provided to this scientiﬁc output.

Suggested citation: EFSA FAF Panel (EFSA Panel on Food Additives and Flavourings), Younes M, Aquilina G, Castle L, Engel K-H, Fowler P, Frutos Fernandez MJ, F€urst P, Gundert-Remy U, G€urtler R, Husøy T, Moldeus P, Oskarsson A, Shah R, Waalkens-Berendsen I, W€olfle D, Benigni R, Bolognesi C, Chipman K, Cordelli E, Degen G, Marzin D, Svendsen C, Martino C and Mennes W, 2020. Scientific Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear, a,b-unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting) structurally related to flavouring substances evaluated in FGE.05Rev3. EFSA Journal 2020;18(1):5924, 44 pp.https://doi.org/10.2903/j.efsa.2020.5924

ISSN: 1831-4732

This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modiﬁcations or adaptations are made.

The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union.

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1. Introduction

The revision of this Flavouring Group Evaluation (FGE) concerns the inclusion of 30a,b-unsaturated carbonyl substances (or precursors thereof; [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841]), which have been evaluated with respect to genotoxicity in FGE.200Rev1. According to the Mandate and Terms of Reference from this FGE, when for a ﬂavouring substance the concern for genotoxicity is ruled out, the European Food Safety Authority (EFSA) proceeds to the full evaluation of these ﬂavouring substances, taking into account the requirements of Commission Regulation (EC) No 1565/2000¹ and of Regulation (EU) No 1334/2008.² The mandate and the Terms of Reference for FGE.200Rev1 are cited below.

1.1. Background and Terms of Reference as provided by the requestor

1.1.1. Background to mandate from FGE.200Rev1 (M-2018-0041)

The useflavourings is regulated under Regulation (EC) No 1334/2008² of the European Parliament and Council of 16 December 2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods. On the basis of Article 9(a) of this Regulation, an evaluation and approval are required forflavouring substances.

The Union list of ﬂavourings and source materials was established by Commission Implementing Regulation (EC) No 872/2012.³The list includes a number ofﬂavouring substances for which the safety evaluation should be completed in accordance with Commission Regulation (EC) No 1565/2000.¹

In February 2011, the EFSA Panel had evaluated aﬁrst dossier submitted by Industry in response to the requested data for representative substances in FGE. 200. These data were not considered adequate to alleviate the genotoxicity concern for the substance in subgroup 1.1.1 and the Panel recommended at that time‘to perform in vivo dietary Comet assays (in drinking water or in feed, not by gavage) for the three linear representatives of subgroup 1.1.1 [FL-no: 05.073, 05.058 and 05.060]’.

Additional data was submitted in February and June 2013 by Industry related to one representative substance of subgroup 1.1.1, hex-2(trans)-enal [FL-no: 05.073] and two other substances of the group.

On 21 May 2014 the EFSA CEF Panel adopted an opinion on this Flavouring Group Evaluation 200 (FGE.200). The Panel conﬁrmed the need for an in vivo Comet assay performed in duodenum and liver for hex-2(trans)-enal [FL-no: 05.073]. For the two representative substances of subgroup 1.1.1 (nona- 2(trans), 6(cis)-dienal [FL-no: 05.058] and oct-2-enal [FL-no: 05.060]), a combined in vivo Comet assay and micronucleus assay would be required and that evidence of bone marrow exposure should be provided.

New data concerning the three representative substances of this group addressing the EFSA opinion have been submitted during 2017. The data also included updated poundage and use levels concerning these substances.

The list of the substances referred to in this letter is included in Annex II.⁴

1.1.2. Terms of Reference of Mandate from FGE.200Rev1 (M-2018-0041)

The European Commission requests the European Food Safety Authority (EFSA) to evaluate the new information submitted and, depending on the outcome, proceed to full evaluation of the substances in this group in accordance with Commission Regulation (EC) No 1565/2000. In accordance with the usual practice by the CEF Panel,⁵ the ﬁrst step (assessment of the genotoxicity) should be

1 Commission Regulation (EC) No 1565/2000 of 18 July 2000 laying down the measures necessary for the adoption of an evaluation programme in application of Regulation (EC) No 2232/96. OJ L 180, 19.7.2000, p. 8–16.

2 Regulation (EC) No 1334/2008 of the European Parliament and of the Council of 16 December 2008 onﬂavourings and certain food ingredients with ﬂavouring properties for use in and on foods and amending Council Regulation (EEC) No 1601/91, Regulations (EC) No 2232/96 and (EC) No 110/2008 and Directive 2000/13/EC. OJ L 354, 31.12.2008, p. 34–50.

3 Commission implementing Regulation (EU) No 872/2012 of 1 October 2012 adopting the list ofﬂavouring substances provided for by Regulation (EC) No 2232/96 of the European Parliament and of the Council, introducing it in Annex I to Regulation (EC) No 1334/2008 of the European Parliament and of the Council and repealing Commission Regulation (EC) No 1565/2000 and Commission Decision 1999/217/EC. OJ L 267, 2.10.2012, p. 1–161.

4 Annex II refers here to the annex of the mandate letter from the EC to EFSA related to FGE.200Rev1.

5 CEF Panel was responsible for the evaluation ofﬂavouring substances at the time when the Mandate was received by EFSA from European Commission.

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completed within nine months. An additional 9 months if necessary is also established for the second step (evaluation through the CEF Procedure).

In case the genotoxic potential cannot be ruled out or the procedure cannot be applied in theﬁrst step, EFSA is asked to quantify the exposure.

1.2. Interpretation of the Terms of Reference

Flavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] were ﬁrst allocated to FGE.200Rev1 for evaluation with respect to genotoxicity. Based on the new genotoxicity data submitted, the Panel concluded that these 30 ﬂavouring substances do not give rise to concern with respect to genotoxicity and can accordingly be evaluated through the Procedure in the present revision 1 of FGE.71 (FGE.71Rev1), in accordance with Commission Regulation (EC) No 1565/2000.

The above-mentioned ﬂavouring substances belong to a group of structurally related substances which had been evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in the past (JECFA, 2005a, 2008a). Other substances in this group have already been considered by EFSA in FGE.71 (EFSA CEF Panel, 2010). For substances already evaluated by JECFA, a full evaluation is not required but EFSA should consider whether the JECFA evaluation can be agreed to or not. If not, EFSA should carry out a full evaluation of such substances (for further explanations see Appendix A).

In addition, since the publication of FGE.71, data on EU production volumes have been provided by industry for the following four ﬂavouring substances [FL-no: 08.073, 08.123, 09.157 and 09.239] and therefore their safety evaluation through the Procedure can also be ﬁnalised in the current revision.

1.2.1. History of the evaluation of the substances in FGE.71

The FGE.71 includes linear aliphatica,b-unsaturated aldehydes, acids and related alcohols, acetals and esters, which have been evaluated before by JECFA in a group of 37 substances at their 63rd meeting (JECFA, 2005a).

Twenty-three substances are a,b-unsaturated aldehydes, or precursors, thereof considered by the Panel to be of concern for genotoxicity. They have been considered, together with other a,b- unsaturated aldehydes and precursors, in FGE.200 (EFSA CEF Panel, 2014) for which aﬁnal conclusion on genotoxicity could not be reached and additional data were requested. Five JECFA-evaluated substances (JECFA numbers 1370, 1371, 1379, 1380 and 1382) were not in the Register⁶ and were not further considered in FGE.71. Therefore, FGE.71 only dealt with nine a,b-unsaturated acids or esters ([FL-no: 08.054, 09.239, 09.235, 09.158, 09.157, 09.156, 09.037, 08.123, 08.073]).

The EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) concluded that these nine ﬂavouring substances are structurally related to the group of branched- and straight-chain unsaturated carboxylic acids and esters of these and straight-chain aliphatic saturated alcohols evaluated by EFSA in the Flavouring Group Evaluation 05, Revision 2 (FGE.05Rev2).

The CEF Panel agreed with the way the application of the Procedure has been performed by JECFA for all nine substances in the group of aliphatic a,b-unsaturated acids and related esters. However, for ﬁve substances, the Panel had reservations (no European production volumes available for [FL-no:

08.073, 08.123, 09.157 and 09.239] preventing them to be evaluated using the Procedure, and missing data on stereoisomerism for [FL-no: 08.073 and 09.235]). For the remaining four substances [FL-no: 08.054, 09.156, 09.158 and 09.037], the Panel agreed with the JECFA conclusion ‘No safety concern at estimated levels of intake as ﬂavouring substances’, based on the ‘Maximised Survey- derived Daily Intake’(MSDI) approach.

For all nine substances evaluated through the Procedure, use levels were needed to calculate the

‘modified Theoretical Added Maximum Daily Intake’ (mTAMDI) estimates in order to identify those flavouring substances that need more refined exposure assessment and to finalise the evaluation.

From the substances considered in the present revision 1 of FGE.71 (FGE.71Rev.1), 23 ﬂavouring substances [FL-no: 02.112, 02.156, 02.210, 02.020, 02.050,02.090, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 09.276, 09.277, 09.394, 09.395, 09.396, 09.398, 09.399] were evaluated by JECFA at its 63rd meeting (JECFA, 2005a) and 10 of these substances [FL-no:

02.050, 02.112, 02.156, 02.210, 09.276, 09.277, 09.395, 09.396, 09.398, 09.399] were re-evaluated by JECFA at its 69th meeting (JECFA, 2008a). These 23 candidate substances were evaluated by EFSA in

6 Commission Decision 1999/217/EC.

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FGE.200Rev1 (EFSA FAF Panel, 2018), where it was concluded that for these substances a concern for genotoxicity could be ruled out. Therefore, they could be evaluated through the Procedure.

In addition, FGE.71Rev1 also deals with seven ﬂavouring substances [FL-no: 02.137, 05.179, 09.303, 09.385, 09.397, 09.678 and 09.841] evaluated by JECFA at its 69th meeting (JECFA 2008a).

By expert judgement, they have been included in FGE.71Rev1 on the basis of their structural similarities with the substances considered in this group. These ﬂavouring substances were also considered of no genotoxic concern in FGE.200Rev1 (EFSA FAF Panel, 2018). Therefore, they can be evaluated through the Procedure.

Together with the nine substances that were already considered in FGE.71, the current revision comprises 39 substances. The four flavouring substances, for which the evaluation was finalised in FGE.71, will not be further discussed. The missing EU production volumes and/or information on stereoisomeric composition for five flavouring substances [FL-no: 08.073, 08.123, 09.157, 09.235 and 09.239], considered in the previous revision (FGE.71), have been provided by industry (Documentation provided to EFSA nr: 3). This information will be included and considered in this revision (FGE.71Rev1).

Nevertheless, for the sake of completion the information for all 39 substances is maintained in the various tables in this FGE.

FGE Adopted by EFSA Link No. of

Substances FGE.71 25 November 2009 https://www.efsa.europa.eu/efsajournal/pub/1205 9

FGE.71Rev1 14 November 2019 https://www.efsa.europa.eu/efsajournal/pub/5924 39 FGE: Flavouring Group Evaluation.

2. Data and methodologies

2.1. Data

The present opinion is based on the data presented in the Table1.

Table 1: Data considered in the current revision 1 of FGE.71

FL-no Chemical name

Data provided for the current revision 1 of FGE.71

Appendix (Table nr) and relevant section of the opinion

Documentation provided to EFSA nr/Reference 02.020 Hex-2-en-1-ol Speciﬁcations,

EU poundage data (MSDI), use levels (mTAMDI), ADME data

AppendixB(TableB.1) AppendixC(TableC.1 andC.4)

Sections3.3.1.

Documentation provided to EFSA nr:

1, 2, 5 02.050 Pent-2-en-1-ol

02.090 Non-2(trans)-en-1-ol 02.112 Non-2(cis)-en-1-ol 02.137 Dec-2-en-1-ol 02.156 Hex-2(cis)-en-1-ol 02.210 Undec-2-en-1-ol 05.037 2-Dodecenal 05.060 Oct-2-enal 05.070 2-Heptenal

05.073 Hex-2(trans)-enal Speciﬁcations,

EU poundage data (MSDI), use levels (mTAMDI), ADME,

toxicity data

Sections3.3.1.

AppendixE(TableE.1)

1, 2, 5.

Gaunt et al., 1971;

Ping et al., 2003;

Stout et al., 2008

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In addition, the following data have been used in FGE.71Rev1:

– JECFA speciﬁcations for the 30 candidate ﬂavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] (JECFA, 2005b, 2008b).

– 63rd and 69th JECFA reports (JECFA, 2005a, 2008a) and 63rd JECFA toxicology monograph (JECFA, 2006).

– Genotoxicity data evaluated in FGE.200 (EFSA CEF Panel, 2014) and FGE.200Rev1 (EFSA FAF Panel, 2018).

– EFSA scientiﬁc opinion on FGE.71 (EFSA CEF Panel, 2010).

– EFSA scientiﬁc opinion on FGE.05Rev3 (EFSA FAF Panel, 2019a).

2.2. Methodologies

This opinion was formulated following the principles described in the EFSA Guidance on transparency with regard to scientific aspects of risk assessment (EFSA Scientific Committee, 2009) and following the relevant existing guidance documents from the EFSA Scientific Committee. The assessment strategy applied for the evaluation programme of flavouring substances, as laid down in

FL-no Chemical name

Data provided for the current revision 1 of FGE.71

Appendix (Table nr) and relevant section of the opinion

Documentation provided to EFSA nr/Reference 05.076 Dec-2-enal Speciﬁcations,

EU poundage data (MSDI), use levels (mTAMDI), ADME data

Sections3.3.1.

1, 2, 5 05.078 Tridec-2-enal

05.102 Pent-2-enal 05.109 2-Undecenal 05.150 Hept-2(trans)-enal 05.171 Non-2-enal 05.179 Tetradec-2-enal 09.276 Oct-2-enyl acetate 09.277 Oct-2(trans)-enyl

butyrate

09.303 Hept-2-enyl isovalerate 09.385 Hept-2-enyl acetate 09.394 E-Hex-2-enyl acetate 09.395 E-Hex-2-enyl

propionate

09.396 Hex-2-enyl butyrate 09.397 Hex-2-enyl formate 09.398 Hex-(2E)-enyl

hexanoate 09.399 (2E)-Hexenyl

isovalerate

09.678 Pent-2-enyl hexanoate 09.841 2-Hexenyl octanoate

08.123 trans-2-Heptenoic acid EU poundage data (MSDI) AppendixC(TableC.4) Documentation provided to EFSA nr: 4 09.157 Ethyl 2-nonynoate

09.239 Methyl 2-undecanoate

08.073 Dec-2-enoic acid Speciﬁcations

EU poundage data (MSDI)

AppendixB(TableB.1) AppendixC(TableC.4)

Documentation provided to EFSA nr: 4 09.235 Butyl dec-2-enoate Speciﬁcations AppendixB(TableB.1) Documentation

provided to EFSA nr: 4 FL-no: FLAVIS number; FLAVIS: Flavour Information System (database); MSDI: Maximised Survey-derived Daily Intake;

mTAMDI: modiﬁed Theoretical Added Maximum Daily Intake; ADME: absorption, distribution, metabolism, and excretion.

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Commission Regulation (EC) No 1565/2000, is based on the Opinion on a Programme for the Evaluation of Flavouring substances of the Scientiﬁc Committee on Food (SCF, 1999).

2.2.1. Procedure for the safety evaluation of ﬂavouring substances

The approach for safety evaluation of chemically deﬁned ﬂavouring substances as referred to in Commission Regulation (EC) No 1565/2000, named the‘Procedure’, is described in Appendix A.

2.2.2. Approach used for the calculation of exposure

The approach used for calculation of the intake of the ﬂavouring substances is described in Appendix A(see point‘a) Intake’) and in AppendixC(Section C.2‘mTAMDI calculation’).

3. Assessment

3.1. Speci ﬁ cations

JECFA status

The JECFA speciﬁcations are available for all 39 ﬂavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 08.054, 08.123, 08.073, 09.239, 09.235, 09.158, 09.157, 09.156, 09.037, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] considered in the present opinion (FGE.71Rev1) (JECFA, 2005b; JECFA, 2008b).

EFSA considerations

Table2 shows the chemical structures of the candidate substances which are considered in this revision of FGE.71 (FGE.71Rev1).

Table 2: Flavouring substances under evaluation in FGE.71Rev1

[FL-no] UL chemical name Structural formula Structural class^(a)

02.020 Hex-2-en-1-ol I

02.050 Pent-2-en-1-ol I

02.090 Non-2(trans)-en-1-ol I

02.112 Non-2(cis)-en-1-ol I

02.137 Dec-2-en-1-ol I

02.156 Hex-2(cis)-en-1-ol I

02.210 Undec-2-en-1-ol I

05.037 2-Dodecenal I

05.060 Oct-2-enal I

05.070 2-Heptenal I

05.073 Hex-2(trans)-enal I

05.076 Dec-2-enal I

05.078 Tridec-2-enal I

05.102 Pent-2-enal I

05.109 2-Undecenal I

05.150 Hept-2(trans)-enal I

05.171 Non-2-enal I

05.179 Tetradec-2-enal I

09.276 Oct-2-enyl acetate I

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The 30 newly included flavouring substances (Table 2) can exist as geometrical stereoisomers due to the presence of a double bond (a,b unsaturation). For 13 flavouring substances ([FL-no: 02.020, 02.050, 02.137, 02.210, 02.102, 05.102, 09.276, 09.303, 09.385, 09.396, 09.397, 09.678 and 09.841]), the chemical name in the Union list (UL) should be changed to reflect the stereochemistry (see ‘EFSA comments’ column in Table B.1 – Appendix B). Additionally, for four substances [FL-no:

02.020, 02.050, 02.137, 02.210 and 05.102], the CAS number in the UL should be changed, as indicated in Table B.1 – AppendixB, according to the updated speciﬁcations provided by industry (Documentation provided to EFSA nr: 1).

The purity requirements for ﬂavouring substances [FL-no: 02.156, 05.073, 09.394 and 09.398]

should be updated according to the speciﬁcations provided by industry (Documentation provided to EFSA nr: 1).

According to the new speciﬁcations provided, the ﬂavouring substances [FL-no: 05.037, 05.060, 05.070, 05.076, 05.078, 05.109 and 05.171] are synonymous with [FL-no: 05.144, 05.190, 05.150, 05.191, 05.195, 05.184 and 05.072] which have been evaluated in FGE.05Rev3 (EFSA FAF Panel, 2019a) and one substance ([FL-no: 05.150]) in the current revision of this FGE (FGE.71Rev1).

Industry informed that two ﬂavouring substances ([FL-no: 08.073 and 09.235], for which EFSA requested in FGE.71 to clarify the stereochemistry, are mixtures of E and Z stereoisomers (Documentation provided to EFSA nr: 4). However, the Panel considered this information not adequate and requests quantitativeﬁgures of the stereoisomers in these mixtures (see ‘EFSA comments’column in Table B.1–Appendix B).

The Panel considered that the available speciﬁcations for the remaining ﬂavouring substances are adequate.

The most recent speciﬁcations data for all 39 substances in FGE.71Rev1 are summarised in Table B.1– AppendixB.

[FL-no] UL chemical name Structural formula Structural class^(a)

09.277 Oct-2(trans)-enyl butyrate I

09.303 Hept-2-enyl isovalerate I

09.385 Hept-2-enyl acetate I

09.394 E-Hex-2-enyl acetate I

09.395 E-Hex-2-enyl propionate I

09.396 Hex-2-enyl butyrate I

09.397 Hex-2-enyl formate I

09.398 Hex-(2E)-enyl hexanoate I

09.399 (2E)-Hexenyl isovalerate I

09.678 Pent-2-enyl hexanoate I

09.841 2-Hexenyl octanoate I

FL-no: FLAVIS number; FLAVIS: Flavour Information System (database); FGE: Flavouring Group Evaluation.

(a): According to OECD (Q)SAR Toolbox (version 4.3).

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3.2. Estimation of intake

JECFA status

For 35 ﬂavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 08.054, 09.235, 09.158, 09.156, 09.037, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841], evaluated through the JECFA Procedure, annual production data are available for the EU (JECFA, 2005a, 2008a).

For the remaining four ﬂavouring substances [FL-no: 08.123, 08.073, 09.157, 09.239], production ﬁgures are only available for the USA.

EFSA considerations

Updated EU production ﬁgures for 30 ﬂavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841] have been submitted by industry (Documentation provided to EFSA nr: 2).

Additionally, for four ﬂavouring substances [FL-no: 08.123, 08.073, 09.157, 09.239], considered in the previous revision of this FGE (FGE.71), EU production volumes have been provided (Documentation provided to EFSA nr: 4) and therefore the EU MSDI values can now be calculated. The MSDI values range from 0.012 to 2,800 lg/capita per day (see TableC.4–Appendix C).

For the 30 newly allocated ﬂavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841], normal and maximum use levels have been submitted by industry (Documentation provided to EFSA nr: 1) and mTAMDI values can be calculated.

The mTAMDI intake estimates for 28flavouring substances, for which use levels were provided (see above), were below the threshold of concern for their structural class (I). For two flavouring substances [FL-no: 02.020 and 05.076], the mTAMDI intake estimates were above the threshold of concern for their structural class (I). For these two substances, more reliable data on use levels should be provided in order to refine the exposure assessment and to finalise their safety evaluation.

No normal and maximum use levels have been provided for the nineﬂavouring substances ([FL-no:

08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235 and 09.239]) previously considered in FGE.71.

The MSDI ﬁgures and mTAMDI intake estimates for the 39 ﬂavouring substances in FGE.71Rev1 are shown in Table C.4–Appendix C.

3.3. Biological and toxicological data

3.3.1. ADME data

According to JECFA (63rd and 69th meeting), all the 30 flavouring substances additionally considered in the present revision (FGE.71Rev1) are expected to be metabolised to innocuous products through normal fatty acid metabolism, including b-oxidation and citric acid cycle, whichfinally leads to their total oxidation. In addition to the oxidative metabolism, also conjugation with glutathione (GSH) has been described. The relevant data are available in the 63rd and 69th JECFA toxicology monograph (JECFA, 2006, 2009) and in FGE.200Rev1 (EFSA FAF Panel, 2018). Based on this information, JECFA concluded that these flavouring substances, which are subject of this revision of FGE.71, can be evaluated along the A-side of the Procedure (see Appendix A).

In addition, in the literature, two publications were found regarding a physiologically basedin silico model for detoxification of the candidate substance trans-2-hexenal [FL-no: 05.073] (Kiwamoto et al., 2012; Kiwamoto et al., 2013). A physiologically based in silico model for the rat was developed for trans-2-hexenal [FL-no: 05.073] to examine the time- and dose-dependent detoxification. The model was evaluated against in vivo data from the literature. A rapid detoxification, mainly by conjugation with GSH, was revealed at an exposure of 0.04 mg/kg bw, estimated to correspond to the daily human dietary intake for this substance. This estimate is in concordance with the MSDI and mTAMDI estimates for this substance (i.e. 2,800 and 1,400 lg/person per day or 0.05 and 0.02 mg/kg bw per day).

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EFSA consideration

Based on the information provided by JECFA and taking into account the outcome of the evaluation of the genotoxicity which also includes potential DNA binding, as described in Section 3.3.2, the Panel agrees with JECFA and considers that these ﬂavouring substances would be expected to be biotransformed into innocuous metabolites.

The data above mentioned are available in FGE.200Rev1 (EFSA FAF Panel, 2018).

3.3.2. Genotoxicity data

This revision involves the inclusion of 30 flavouring substances [FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841]), for which in FGE.19 a concern for genotoxicity had been identified based on the presence of a structural alert (i.e. a,b-unsaturated carbonyl or precursor for that), preventing their evaluation through the Procedure (see also Appendix A). Because of this, these 30 flavouring substances needed further attention in FGE.200.

The genotoxicity, which also includes the potential DNA binding of theseﬂavouring substances, has been assessed in FGE.200 (EFSA CEF Panel, 2014) and FGE.200Rev.1 (EFSA FAF Panel, 2018). Based on the genotoxicity data submitted, the Panel ruled out genotoxicity concerns for these ﬂavouring substances.

Therefore, it is concluded that all 30ﬂavouring substances can be evaluated through the Procedure in the current revision 1 of FGE.71.

3.3.3. Toxicological data

3.3.3.1. Repeated dose toxicity studies

In the 63rd JECFA toxicology monograph (JECFA, 2006), detailed descriptions on short-term toxicity studies with some of the ﬂavouring substances belonging to FGE.71 ([FL-no: 09.037 and 05.073] are available. In particular for ﬂavouring substance [FL-no: 05.073], under evaluation in this revision, a 13- week toxicity study is available (Gaunt et al., 1971) from which a no observed adverse effect level (NOAEL) could be derived. A 28-day study in rats following gavage administration of [FL-no: 05.073]

(Stout et al., 2008) was also reported in the 69th JECFA safety evaluation ofﬂavouring agents (JECFA, 2008a). Additionally, for trans-2-hexenal [FL-no: 05.073], a study related to cardiotoxicity in mice following trans-2-hexenal exposure was also considered (Ping et al., 2003).

A 14-week NTP (National Toxicology Program) study in rats and mice on a structurally related substance (NTP, 2003), i.e. hexa-2(trans),4(trans)-dienal [05.057]) was evaluated in FGE.70Rev1 (EFSA FAF Panel, 2019b).

The toxicity studies on the candidate substance [FL-no: 05.073] are shortly described below.

All the toxicological studies are summarised in TableE.1–Appendix E.

3.3.3.2. Acute and subacute toxicity studies on trans-2-hexenal [FL-no: 05.073]

Trans-2-hexenal [FL-no: 05.073] (95% minimum purity) was tested in mice (10 males and 10 females) and rats (5 males and 5 females) for acute toxicity after a single dose given both by intraperitoneal (i.p.) injection and by stomach tube. Surviving animals were observed for 14 days after administration of the single dose. LD₅₀ for rats were 780 mg/kg (males) and 1,130 mg/kg (females) and for mice 1,750 mg/kg (males) and 1,550 mg/kg (females) when given by stomach tube. LD₅₀ for rats were 200 mg/kg (males) and 180 mg/kg (females) and for mice 100 mg/kg (males) and 160 mg/

kg (females) when administered intraperitoneally. Subsequently, a palatability test was performed over an 8-day period where pairs of female rats were offered two diets simultaneously – a basal (control) diet and a diet spiked with either 260, 640, 1,600 or 4,000 mg trans-2-hexenal/kg feed. Feed consumption was decreased at 640 mg/kg feed and above (Gaunt et al., 1971).

Trans-2-hexenal (purity 98%) in corn oil was tested in rats at single gavage doses of 0, 50, 200 and 500 mg/kg bw (Stout et al., 2008). Decreased body weights and necroulcerative lesions with inﬂammation in the forestomach were reported at the two highest doses. At 50 mg/kg bw, the damage was minimal. Stout et al. (2008) also administeredtrans-2-hexenal to 4–5 rats per dose group by oral gavage for 5 days or 5 days per week during 4 weeks at doses of 0, 10, 30 and 100 mg/kg bw per day. Hyperplasia of the forestomach was the main effect and reported in increasing incidence and severity in animals administered 10, 30 and 100 mg/kg bw per day.

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With respect to the acute and subacute toxicity studies, the Panel concluded that due to the gavage administration of an irritating substance, these toxicological studies are not suitable for risk assessment ofﬂavouring substances under evaluation in this FGE, including derivation of a NOAEL.

Effects on heart muscle tissue and function were studied by Ping et al. (2003) after single weekly gavage administration of trans-2-hexenal to mice in doses of 0, 0.1, 1, 10 and 50 mg/kg bw per week for 4 weeks. The source and purity of the substance were not reported. According to the authors, the four gavage treatments withtrans-2-hexenal induced some condensed nuclei in the heart and changes that were indicative of impaired left ventricular contractile function. However, the Panel noted the lack of dose response in the effects on cardiac function. In addition, no histopathological ﬁndings in heart tissue were found in subchronic feeding studies with higher doses of this substance in rats (see below). The Panel observed that the study design and the reporting were of poor quality. Therefore, the Panel considered this study not reliable.

3.3.3.3. Subchronic toxicity study on 2-trans-hexenal [FL-no: 05.073]

Rats

In a study by Gaunt et al. (1971), groups of 15 male and 15 female rats (CFE strain), were fed diets containing 0 (control), 260, 640, 1,600 or 4,000 mg trans-2-hexenal/kg feed (corresponding to a mean intake of 0, 18, 45, 110 and 257 mg/kg bw per day for males and 0, 21, 52, 131 and 304 mg/kg bw per day for females as calculated from data on body weight and food consumption by the author) of trans-2-hexenal for 13 weeks. Body weights for individual animals and food consumption per cage were recorded weekly. Speciﬁc gravity and volume were determined in urine after water deprivation and after an oral water load. Collected urine sampled during a 6 hours period was analysed for protein, glucose, bile salts, ketones, blood, microscopic constituents and aspartate transaminase (AST) concentration.

Blood for haematology (haemoglobin concentrations, packed cell volumes, erythrocyte counts, reticulocytes, total leucocytes and various types of leucocytes) was collected at week 6 from eight males and eight females from groups fed 0, 1,600 and 4,000 mg/kg, and at autopsy at week 13 from all treated animals (serum analysis of urea content and alanine transaminase (ALT) and AST). At autopsy, gross lesions were recorded and brain, pituitary, thyroid, heart, liver, spleen, adrenal glands, kidneys and gonads were sampled and weighed. For control and high-dose animals, samples of weighed organs as well as lymph nodes, thymus, urinary bladder, stomach, duodenum, ileum, colon, caecum, rectum, pancreas, uterus and skeletal muscle from control and highest treated groups were examined by histopathology.

No abnormalities in clinical observations were seen and no differences in feed consumption were reported between groups fed control or test diets except at the high dose, where the feed intake was statistically lower (p < 0.01) both for males and females.

In males, there was a slight but statistically signiﬁcant decrease in haemoglobin concentration at six weeks (4,000 mg/kg diet) and at 13 weeks (1,600 mg/kg diet). There was also a statistically signiﬁcant decrease in red blood cell counts in some dose groups in males, although not dose- dependent. The Panel considered the haematological effects to be spurious and not treatment-related.

The only parameter in the urine analysis which showed statistically signiﬁcant results was a lower speciﬁc gravity in high-dose males compared to controls under condition of dehydration. However, there were no indications of renal dysfunction based on other urinary function parameters or from histopathology of the kidney.

There were no dose-related effects on organ weights or treatment-related effects on histopathology, although statistically signiﬁcant increased ovary weights were observed in all treated female rats (approximately 20–30%). However, no histological abnormalities were seen in the ovaries and the effects on ovary weights were not conﬁrmed in a supplementary study in female rats fed 4,000 mg/kg of trans-2-hexenal in the diet. Neither there were any effects on the number of corpora lutea or on the oestrus cycle in the supplementary study.

Rabbits

In order to address theﬁndings of increased ovary weights in the 13 weeks study, a limited study was set up in rabbits. Groups of ten female rabbits were given daily doses of 0 (control) or 200 mg/kg bw of trans-2-hexenal via oral intubation for 13 weeks. The animals were weighed weekly. At autopsy, blood was collected for haematology and the brain, heart, liver, spleen, kidneys, stomach, small intestine, ovaries, uterus, pituitary and adrenal glands were weighed. The same tissues as listed in the

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13 weeks rat study were sampled and prepared for histopathology. A statistically signiﬁcant decrease in haemoglobin concentration was observed in the rabbits administered trans-2-hexenal as well as an increase in absolute and relative stomach weight. The latter ﬁndings were associated with signs of ulceration and haemorrhage in the gastric mucosa of the dosed animals and were, according to the author, probably due to high local concentrations of the test compound resulting from oral intubation and the irritant nature of the test compound. The Panel agrees with the explanation. No changes in the weight or microscopic appearance of the ovaries, uterus or endocrine organs were observed compared to controls.

EFSA consideration

Overall, the Panel noted that no dose-related adverse effects were revealed in the 90-day rat toxicity study by Gaunt et al. (1971), where trans-2-hexenal [FL-no: 05.073] was administered in the diet. With respect to the subchronic toxicity study by Gaunt, the Panel considered the NOAEL of this study to be the highest dose tested, corresponding to 257 mg/kg bw per day in males and 304 mg/kg bw per day in females, which is supported by the absence of systemic toxicity in a 13 weeks toxicity study in rabbits, given 200trans-2-hexenal mg/kg bw per day by gavage.

3.4. Application of the procedure

Application of the Procedure to aliphatic, a,b-unsaturated linear aldehydes, acids and related alcohols, acetals and esters by JECFA (JECFA, 2005a; JECFA,2008a)

In the respective meeting reports where the 30 additional ﬂavouring substances included in this revision of FGE.71 are discussed ([FL-no: 02.020, 02.050, 02.090, 02.112, 02.137, 02.156, 02.210, 05.037, 05.060, 05.070, 05.073, 05.076, 05.078, 05.102, 05.109, 05.150, 05.171, 05.179, 09.276, 09.277, 09.303, 09.385, 09.394, 09.395, 09.396, 09.397, 09.398, 09.399, 09.678 and 09.841]), JECFA allocated all these ﬂavouring substances to structural class I using the decision tree approach presented by Cramer et al. (Cramer et al., 1978).

JECFA concluded for all 30 candidate ﬂavouring substances that these can be anticipated to be metabolised to innocuous products (step 2) and the intakes (MSDIs) for all substances are below the threshold of concern for their structural class I (i.e. 1,800 lg/person per day) (step A3).

In conclusion, JECFA evaluated all the 30 candidate substances as to be of no safety concern at the estimated levels of intake as ﬂavouring substances based on the MSDI approach.

The JECFA safety evaluations of theﬂavouring substances are summarised in TableD.1–Appendix D.

EFSA considerations

The FAF Panel agrees with JECFA with respect to the allocation of the candidate ﬂavouring substances to Cramer class I.

In line with JECFA, the Panel considers all the 30 newly included flavouring substances to be expected to be metabolised to innocuous products (step 2) and accordingly to evaluate these substances along the A-side of the Procedure. The same conclusion was also reached for four flavouring substances [FL-no: 08.073, 08.123, 09.157 and 09.239], considered in FGE.71 (EFSA CEF Panel, 2010), for which the assessment could not be finalised due to lacking information on exposure.

The estimated daily intake, based on MSDI approach, of all ﬂavouring substances is below the threshold of concern for their structural class I (step A3), except for [FL-no: 05.073]. The MSDI value, based on updated EU poundage data, for trans-2-hexenal [FL-no: 05.073] is above the threshold of concern for structural class I (2,800 lg/person per day vs. 1800lg/person per day).

The Panel considers that the available NOAEL for trans-2-hexenal [FL-no: 05.073] (i.e. 257 mg/kg bw per day in male rats and 304 mg/kg bw per day in female rats, Gaunt et al., 1971) provides an adequate margin of safety (> 5,000).

Therefore, the Panel agrees with the evaluation for 29 ﬂavouring substances as performed by JECFA, i.e. the substances are expected to be metabolised to innocuous products (step 2) and the estimated daily intake, based on MSDI approach, is below the threshold of concern for their structural class I (step A3). The Panel deviates from JECFA in the evaluation of ﬂavouring substance [FL-no:

05.073]. The Panel concludes [FL-no: 05.073] at step A5 of the Procedure scheme, i.e. the substance is not endogenous (step A4) and a NOAEL for the candidate substance, which provides an adequate margin of safety under conditions of intended use, exists (step A5).

For the fourﬂavouring substances [FL-no: 08.073, 08.123, 09.157 and 09.239], already considered in FGE.71, EU production volumes became available after publication of the FGE.71 (EFSA CEF Panel,

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2010). The MSDI exposure estimates for these four substances range from 0.012 to 4 lg/capita per day and they are all below the threshold of concern for their structural class I. At step A3 of the Procedure it can be concluded that these substances do not raise a safety concern under their intended conditions of use.

Overall in this revision 1 of FGE.71, the Panel evaluates all 30 additional candidate substances and four substances, for which the assessment could not be ﬁnished in FGE.71, as of no safety concern at the estimated levels of intake asﬂavouring substances based on MSDI approach.

The stepwise evaluations of the 34 substances are summarised in TableD.1–Appendix D.

4. Discussion

This revision 1 of FGE.71 comprises in total 39 substances, 9 of which had already been considered in FGE.71. The additional 30 ﬂavouring substances have been included in this revision, following an extensive evaluation in FGE.200Rev1 of their possible genotoxic potential due to a structural alert for genotoxicity (i.e. a,b unsaturated carbonyl compounds or precursors for that). Five of the previously considered substances in FGE.71 have been reconsidered because of additional information.

Based on absence of genotoxic potential in vivo, consideration of structural class, metabolism and toxicological data and the MSDI exposure estimates, the FAF Panel concludes that the ﬂavouring substances considered in this revision of FGE.71 (FGE.71Rev1) do not raise a safety concern at step A3 and one substance (trans-2-hexenal [FL-no: 05.073]) at step A5 of the Procedure scheme, for which an available NOAEL provides an adequate margin of safety.

For all 30 newly addedflavouring substances considered in this FGE.71Rev1, normal and maximum use levels have been provided, from which mTAMDI exposure estimates have been calculated. For all these newly added substances, the mTAMDI values are below the threshold of concern for their structural class I, with the exception of two flavouring substances [FL-no: 02.020 and 05.076] which have the mTAMDI values above the threshold of concern for their structural class (I). For these two substances, more detailed information on uses and use levels is necessary to refine the exposure assessment and to finalise the evaluation. For the previously considered (in FGE.71) nine substances [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235 and 09.239], no normal or maximum use levels have been provided. For these nine substances, use levels are needed to calculate the mTAMDIs in order to identify those flavouring substances that need more refined exposure assessment and tofinalise their evaluation.

In order to determine whether the conclusion for the 39 JECFA-evaluated substances can be applied to the materials of commerce, it is necessary to consider the available specifications. Adequate specifications, including complete purity criteria and identity data, are available for 37 JECFA-evaluated substances. For two substances [FL-no: 08.073 and 09.235], the information on the composition of the stereoisomeric mixtures is incomplete. According to the new specifications provided, the flavouring substances [FL-no: 05.037, 05.060, 05.070, 05.076, 05.078, 05.109 and 05.171] are synonymous with [FL-no: 05.144, 05.190, 05.150, 05.191, 05.195, 05.184 and 05.072] which have been evaluated in FGE.05Rev3 and one substance ([FL-no: 05.150]) in the current revision of FGE.71.

5. Conclusions

For 37 flavouring substances in FGE.71Rev1, the Panel agrees with JECFA conclusions ‘No safety concern at estimated levels of intake as flavouring substances’ based on the MSDI approach. For the remaining two flavouring substances [FL-no: 08.073 and 09.235], the Panel has reservations as there is incomplete information on their chemical identity (composition of the stereoisomeric mixtures is lacking). For the previously considered (in FGE.71) nine substances [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235 and 09.239], no normal or maximum use levels have been provided. For two flavouring substances [FL-no: 02.020 and 05.076], the mTAMDI estimates are above the TTC for their structural class I. Therefore, additional information on uses and use levels should be provided for these eleven substances in order tofinalise their evaluation.

6. Recommendations

The Panel recommends the European Commission to consider:

•

to request normal and maximum use levels for [FL-no: 08.054, 08.073, 08.123, 09.037, 09.156, 09.157, 05.158, 09.235 and 09.239];

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•

to request more reliable data on uses and use levels for [FL-no: 02.020 and 05.076], as the mTAMDI exposure estimates are above the threshold of concern for their structural class I;

When the above data are received, the assessment for these ﬂavouring substances should be updated accordingly and expanded if necessary (i.e. request of additional toxicology data);

•

to change the chemical names in the Union List for 13 ﬂavouring substances ([FL-no: 02.020, 02.050, 02.137, 02.210, 02.102, 05.102, 09.276, 09.303, 09.385, 09.396, 09.397, 09.678 and 09.841]) to reﬂect the stereochemistry (see TableB.1 –Appendix B);

•

to change the CAS number in the Union List for ﬁve substances [FL-no: 02.020, 02.050, 02.137, 02.210 and 05.102], as indicated in Table B.1 –Appendix B, according to the updated speciﬁcations provided;

•

to update the purity requirements forﬂavouring substances [FL-no: 02.156, 05.073, 09.394 and 09.398] as indicated in TableB.1–Appendix B, according to the updated speciﬁcations provided;

•

to delete seven ﬂavouring substances from the Union List because [FL-no: 05.037, 05.060, 05.070, 05.076, 05.078, 05.109 and 05.171] are synonymous with [FL-no: 05.144, 05.190, 05.150, 05.191, 05.195, 05.184 and 05.072]. It is further recommended to request information from industry which of these synonymous substances should be deleted. For the substances that will remain in the Union List, adequate speciﬁcations and data on uses and normal and maximum use levels should be provided, because the available information on these substances is not fully consistent;

•

to request data on the composition of the stereoisomeric mixture for [FL-no: 08.073 and 09.235].

Documentation provided to EFSA

1) EFFA (European Flavour Association), 2019. EFFA Submission of additional information on isomeric composition of substances within FGE.71Rev1 (FGE.19 Subgroup 1.1.1) and reﬁned use levels.

2) EFFA (European Flavour Association), 2018a. EFFA 2015 poundage information for 74 substances from FGE.19 subgroup 1.1.1 corresponding to FGE.200. Unpublished data submitted from EFFA to EFSA. Dated August 2018.

3) EFFA (European Flavour Association), 2017a. Use levels survey for 84 substances from FGE.200. Unpublished data submitted from EFFA to EFSA. Dated 31/07/17.

4) EFFA (European Flavour Association), 2010. EFFA Letter to EFSA on EFSA questions on FGE.71 (The EFSA Journal (2010), 8(2):1401). Dated 19/04/2010.

5) EFFA (European Flavour Association), 2017. Submission by the European Flavour Association to the European Food Safety Authority. Flavouring Group Evaluation 19 Subgroup 1.1.1 (corresponding to FGE.200): Addendum to Flavouring Group Evaluation 19 Subgroup 1.1.1: 74 Flavouring Substances (Flavouring Substances) of the Chemical Group 3 (Annex I of 1565/2000/

EC) Structurally Related to Straight-Chain Aliphatic Acyclic alpha,beta-Unsaturated Aldehydes, with or without Non Conjugated Double Bonds, Used as Flavouring Substances. 14 August 2017.

6) EFFA (European Flavour Association), 2002. Letter from EFFA to Dr. Joern Gry, Danish Veterinary and Food Administration. Dated 31 October 2002. Re.: Second group of questions. FLAVIS/8.26.

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JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2008b. Compendium of food additive speciﬁcations.

Joint FAO/WHO Expert Committee of Food Additives. 69th meeting 2008. Rome, 2008. FAO JECFA Monograph 5.

JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2009. Safety evaluation of certain food additives and contaminants. Sixty-ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series: 60. IPCS, WHO, Geneva.

JECFA (Joint FAO/WHO Expert Committee on Food Additives), 2016. Evaluation of certain food additives, eighty- second report of the Joint FAO/WHO Expert Committee on Food Additives, WHO technical report series; no.

1000, 2016, Geneva, Switzerland.

Kiwamoto R, Rietjens MCM and Punt A, 2012. A physiologically based in silico model for trans-2-hexenal detoxiﬁcation and DNA adduct formation in rat. Chemical Research in Toxicology, 25, 2630–2641.

Kiwamoto R, Spenkelink A, Rietjens IMCM and Punt A, 2013. A physiologically based in silico model for trans‑2‑hexenal detoxification and DNA adduct formation in human including interindividual variation indicates efficient detoxification and a negligible genotoxicity risk. Archives of Toxicology, 87, 1725–1737.https://doi.org/

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NTP (National Toxicology Program), 2003. Toxicology and carcinogenesis studies of 2,4-hexadienal in F344/N rats and B6C3F1 mice (gavage studies). NTP TRS 509, NIH Publication No. 04–4443. Available online:http://ntp.nie hs.nih.gov/ntp/htdocs/LT_rpts/tr509.pdf

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Ping P, Baines CP, Gu Y, Prabhu SD, Zhang J, Tsai LL, Cardwell E, Zong NC, Vondriska TM, Korge P, Bhatnagar A and Wang GW, 2003. Cardiac Toxic Effects of Trans-2-Hexenal Are Mediated by Induction of Cardiomyocyte Apoptotic Pathways. Cardiovascular Toxicology, 3, 341–351.

SCF (Scientific Committee on Food), 1995. Scientific Committee for Food. First annual report on chemically defined flavouring substances. May 1995, 2nd draft prepared by the SCF Working Group on Flavouring Substances (Submitted by the SCF Secretariat, 17 May 1995). CS/FLAV/FL/140-Rev2. Annex 6 to Document III/5611/95, European Commission, Directorate-General III, Industry.

SCF (Scientiﬁc Committee on Food), 1999. Opinion on a programme for the evaluation of ﬂavouring substances (expressed on 2 December 1999). SCF/CS/FLAV/TASK/11 Final 6/12/1999. Annex I the minutes of the 119th Plenary meeting. European Commission, Health & Consumer Protection Directorate-General.

Stout MD, Bodes E, Schoonhoven R, Upton PB, Travlos GS and Swenberg JA, 2008. Toxicity, DNA Binding, and Cell Proliferation in Male F344 Rats following Short-term Gavage Exposures to Trans-2-Hexenal. Toxicologic Pathology, 36, 232–246.

Abbreviations

ADME absorption, distribution, metabolism, and excretion ALT alanine transaminase

AST aspartate transaminase

BW body weight

CAS Chemical Abstract Service

CEF Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids CoE Council of Europe

EFFA European Flavour Association

FAO Food and Agriculture Organization of the United Nations FEMA Flavor and Extract Manufacturers Association

FGE Flavouring Group Evaluation

FLAVIS (FL) Flavour Information System (database)

GSH glutathione

ID identity

i.p. intraperitoneal IR infrared spectroscopy

JECFA The Joint FAO/WHO Expert Committee on Food Additives LD₅₀ lethal dose, median

MS mass spectrometry

MSDI maximised survey-derived daily intake

mTAMDI modiﬁed Theoretical Added Maximum Daily Intake NMR nuclear magnetic resonance

No number

NOAEL No observed adverse effect level

(Q)SAR (quantitative) structure–activity relationship SCF Scientiﬁc Committee on Food

TTC threshold of toxicological of concern WHO World Health Organization

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Appendix A – Procedure of the safety evaluation

The approach for a safety evaluation of chemically defined flavouring substances as referred to in Commission Regulation (EC) No 1565/2000, named the ‘Procedure’, is shown in schematic form in FigureA.1. The Procedure is based on the Opinion of the Scientific Committee on Food expressed on 2 December 1999 (SCF, 1999), which is derived from the evaluation Procedure developed by the Joint FAO/WHO Expert Committee on Food Additives at its 44th, 46th and 49th meetings (JECFA, 1995, 1996, 1997, 1999), hereafter named the‘JECFA Procedure’.⁷

The Procedure is a stepwise approach that integrates information on intake from current uses, structure-activity relationships, metabolism and, when needed, toxicity. One of the key elements in the Procedure is the subdivision of ﬂavourings into three structural classes (I, II and III) for which toxicological thresholds of concern (TTCs) (human exposure thresholds) have been speciﬁed.

Exposures below these TTCs are not considered to present a safety concern.

Class I contains flavourings that have simple chemical structures and efficient modes of metabolism, which would suggest a low order of oral toxicity. Class II contains flavourings that have structural features that are less innocuous, but are not suggestive of toxicity. Class III comprises flavourings that have structural features that permit no strong initial presumption of safety, or may even suggest significant toxicity (Cramer et al., 1978). The TTCs for these structural classes of 1, 800, 540 or 90 lg/person per day, respectively, are derived from a large database containing data on subchronic and chronic animal studies (JECFA, 1996).

In step 1 of the Procedure, the ﬂavourings are assigned to one of the structural classes. The further steps address the following questions:

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^{Can the}^ﬂavourings be predicted to be metabolised to innocuous⁸products (step 2)?

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Do their exposures exceed the TTC for the structural class (steps A3 and B3)?

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^{Are the}^ﬂavourings or their metabolites endogenous⁸(step A4)?

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Does a NOAEL exist on theﬂavourings or on structurally related substances (steps A5 and B4)?

In addition to the data provided for the ﬂavouring substances to be evaluated (candidate substances), toxicological background information available for compounds structurally related to the candidate substances is considered (supporting substances), in order to assure that these data are consistent with the results obtained after application of the Procedure.

The Procedure is not to be applied to ﬂavourings with existing unresolved problems of toxicity.

Therefore, the right is reserved to use alternative approaches if data on speciﬁc ﬂavourings warranted such actions (Figure A.1).

7 The FAF Panel is aware that a revised Procedure for the Safety Evaluation of Flavouring agents has been agreed by JECFA (JECFA, 2016). The EFSA Scientific Committee has developed a modified procedure for evaluation of substances based on the TTC approach (EFSA Scientific Committee, 2019). However, these developments have no impact on the present evaluation, which should follow the requirements as set out in Commission Regulation (EC) No 1565/2000.

8 Innocuous products: products that are known or readily predicted to be harmless to humans at the estimated intake of the ﬂavouring agent (JECFA, 1997).

Endogenous substances: intermediary metabolites normally present in human tissues andﬂuids, whether free or conjugated;

hormones and other substances with biochemical or physiological regulatory functions are not included. The estimated intake of aﬂavouring agent that is, or is metabolized to, an endogenous substance should be judged not to give rise to perturbations outside the physiological range (JECFA, 1997).

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For the flavouring substances considered in this FGE, the EFSA Panel on Food additives and Flavourings compares the JECFA evaluation of structurally related substances with the result of a corresponding EFSA evaluation, focussing on specifications, intake estimations and toxicity data, especially genotoxicity data. The considerations by EFSA will conclude whether the flavouring substances are of no safety concern at their estimated levels of intake, whether additional data are required or whether certain substances should not be evaluated through the EFSA Procedure.

The following issues are of special importance:

a) Intake

In its evaluation, the Panel as a default uses the ‘maximised survey-derived daily intake’ (MSDI)⁹ approach to estimate the per capita intakes of theﬂavouring substances in Europe.

In its evaluation, the JECFA includes intake estimates based on the MSDI approach derived from both European and USA production figures. The highest of the two MSDI figures is used in the evaluation by the JECFA. It is noted that in several cases, only the MSDI figures from the USA were available, meaning that certain flavouring substances have been evaluated by the JECFA only on the basis of these figures. For substances in the Union List offlavouring substances¹⁰for which this is the case, the Panel will need European Union (EU) productionfigures in order tofinalise the evaluation.

When the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach. It is noted that the JECFA, at its 65th meeting, considered ‘how to improve the identification and assessment offlavouring agents, for which the MSDI Figure A.1: Procedure for the safety evaluation of chemically definedflavouring substances

9 EU MSDI: Amount added to food as ﬂavour in (kg/year) x 10⁹/(0.19population in Europe (= 375910⁶) 90.69365)= µg/capita per day.

10 Commission Implementing Regulation (EU) No 872/2012 of 1 October 2012 adopting the list ofﬂavouring substances provided for by Regulation (EC) No 2232/96 of the European Parliament and of the Council, introducing it in Annex I to Regulation (EC) No 1334/2008 of the European Parliament and of the Council and repealing Commission Regulation (EC) No 1565/2000 and Commission Decision 1999/217/EC. OJ L 267, 2.10.2012, p. 1–161.

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estimates may be substantially lower than the dietary exposures that would be estimated from the anticipated average use levels in foods’(JECFA, 2006).

In the absence of more accurate information that would enable the Panel to make a more realistic estimate of the intakes of the ﬂavouring substances, the Panel has decided also to perform an estimate of the daily intakes per person using a modiﬁed Theoretical Added Maximum Daily Intake (mTAMDI) approach based on the normal use levels reported by Industry (EFSA, 2010).

As information on use levels for theﬂavouring substances has not been requested by the JECFA or has not otherwise been provided to the Panel, it is not possible to estimate the daily intakes using the mTAMDI approach for many of the substances evaluated by JECFA. The Panel will need information on use levels in order toﬁnalise the evaluation.

b) Threshold of 1.5 microgram/person over day (step B5) used by the JECFA

JECFA uses the threshold of concern of 1.5lg/person per day as part of the evaluation procedure:

‘The Committee noted that this value was based on a risk analysis of known carcinogens which involved several conservative assumptions. The use of this value was supported by additional information on developmental toxicity, neurotoxicity and immunotoxicity. In the judgement of the Committee, ﬂavouring substances for which insufﬁcient data are available for them to be evaluated using earlier steps in the Procedure, but for which the intake would not exceed 1.5 microgram per person per day would not be expected to present a safety concern. The Committee recommended that the Procedure for the Safety Evaluation of Flavouring Agents used at the forty-sixth meeting be amended to include the last step on the right-hand side of the original procedure (“Do the condition of use result in an intake greater than 1.5 lg per day?”)’(JECFA, 1999).

In line with the opinion expressed by the SCF (1999), the Panel does not make use of this threshold of 1.5 lg/person per day.

c) Genotoxicity

As reﬂected in the opinion of the SCF (1999), the Panel has in its evaluation focussed on a possible genotoxic potential of the ﬂavouring substances or of structurally related substances. Generally, substances for which the Panel has concluded that there is an indication of genotoxic potential in vitro, will not be evaluated using the EFSA Procedure until further genotoxicity data are provided.

Substances for which a genotoxic potential in vivo has been concluded, will not be evaluated through the Procedure.

d) Speciﬁcations

Regarding speciﬁcations, the evaluation by the Panel could lead to a different opinion than that of JECFA, since the Panel requests information on e.g. isomerism.

e) Structural Relationship

In the consideration of the JECFA-evaluated substances, the Panel will examine the structural relationship and metabolism features of the substances within the ﬂavouring group and compare this with the corresponding Flavouring Group Evaluation (FGE).

Scientific Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear, α,β‐unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting) structurally related to

Scienti ﬁ c Opinion on Flavouring Group Evaluation 71 Revision 1 (FGE.71Rev1): consideration of aliphatic, linear,

a , b -unsaturated alcohols, aldehydes, carboxylic acids, and related esters evaluated by JECFA (63rd and 69th meeting)

structurally related to ﬂ avouring substances evaluated in FGE.05Rev3

Abstract

Table of contents

1. Introduction

1.1. Background and Terms of Reference as provided by the requestor

1.2. Interpretation of the Terms of Reference

2. Data and methodologies

2.1. Data

2.2. Methodologies

3. Assessment

3.1. Speci ﬁ cations

3.2. Estimation of intake

3.3. Biological and toxicological data

3.4. Application of the procedure

4. Discussion

5. Conclusions

6. Recommendations

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Documentation provided to EFSA

References

Abbreviations

Appendix A – Procedure of the safety evaluation

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